47
Journal of Neonatal-Perinatal Medicine 8 (2015) 47–51 DOI 10.3233/NPM-15814078 IOS Press
Original Research
Report of a pilot study of Cooling four preterm infants 32–35 weeks gestation with HIE William F. Walsha,∗ , David Butlerb and John W. Schmidtc a Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt Nashville,
TN, USA b Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, USA c Joint Division of Newborn Medicine, Creighton University Medical Center, Omaha, NE, USA
Received 20 August 2014 Revised 6 November 2015 Accepted 17 December 2014
Abstract. This report reviews the use of the Cool-Cap device to apply selective therapeutic hypothermia to the brain of preterm infants, without causing systemic hypothermia. Four infants, 32–35 weeks gestation, with suspected Hypoxic Ischemic Encephalopathy (HIE) received treatment aimed at providing selective brain cooling. It was not possible to apply cold circulating water to the scalp of the preterm infant without systemic hypothermia unless a warming blanket was also used. All infants had severe HIE and all had either death, or neurologic disability despite cooling attempts. Therapeutic hypothermia cannot be recommended at this time for preterm infants outside clinical trials. Keywords: Hypoxic ischemic encephalopathy, therapeutic hypothermia, cool cap
1. Introduction Hypoxic ischemic encephalopathy (HIE) treatments have been investigated for term infants. HIE, occurring in 2.9–9/1000 term births, is recognized as a major cause of mortality and morbidity in the newborn worldwide [1]. However, there is little research regarding HIE in preterm infants. The majority of term baby HIE occurs secondary to loss of oxygenation due to etiologies such as abruption, prolapsed cord, uterine rupture, ∗ Corresponding author: Dr. William F. Walsh, Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, 2200 Children’s Way, Nashville, TN 37232, USA. Tel.: +1 615 322 0545; Fax: +1 615 343 1883; E-mail: [email protected].
placental insufficiency, and compression of the cord [2]. Adverse neurological outcomes following perinatal anoxic brain injury, such as cerebral palsy, seizure disorders, and neurodevelopmental insults have been reported in over 60% of infants that meet criteria [2]. Furthermore, HIE results in death secondary to multiorgan failure within the neonatal period in 20–30% of term infants with significant asphyxia [2]. Therapeutic hypothermia (TH) is clearly established to improve the medium and long-term outcomes from moderate to severe HIE at term neuroprotective in term infants [3, 4]. Preterm infants were intentionally excluded from the early randomized trials of TH for a number of reasons. HIE is difficult to diagnose in preterm infants due to the confounding effects of prematurity itself on the
1934-5798/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
48
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
neurologic examination, Apgar scores, and the laboratory findings which have been used in term infants to diagnose HIE. In addition, the effects of premature delivery and confounding injuries during prolonged neonatal intensive care on the immature central nervous systems result in neurologic injuries such as periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH). Determining the timing and mechanism of CNS injury in preterm infants is not possible at this time since acquired insults confound the long-term neurologic outcomes in preterm infants [5]. Thus it is difficult to determine any additive impact of perinatal HIE on the neurodevelopmental outcomes of preterm infants. Finally, hypothermia is universally recognized as an adverse experience for the preterm infant associated with increased mortality and morbidity in numerous reports since the original work by Silverman [6]. The California Quality Care Collaborative reported an increased risk of death and IVH in infants less than 1500 grams with moderate short term hypothermia and no one has looked at safety of intentional prolonged hypothermia [7, 8]. For these reasons, the definition of HIE by ACOG and the AAP states that HIE is only applicable for infants >34 completed weeks of gestation [9] and to date all studies of TH have excluded infants less than 35 weeks gestation. We, and others, reported on the definition of HIE in preterm infants [10, 11] and felt that with careful evaluation we could successfully define the preterm infant 32–35 weeks gestation with HIE in order to take the first step toward providing therapy to ameliorate long-term injury. Animal models of hypothermia to prevent progressive CNS injury in preterms are promising. Alistair Gunn demonstrated the potential of hypothermia to ameliorate brain injury in a preterm lamb equivalent to about 29 week’s gestation [12]. Importantly, Thoresen et al. published an intriguing report on the ability to provide selective CNS cooling without systemic hypothermia in a piglet model [13, 14]. Based on these reports we designed a pilot study to determine if it was feasible to cool the scalp and potentially the brain of a preterm human infant without causing systemic hypothermia.
2. Methods Eligible infants were babies over 1500 grams and over 32 0/7 weeks and less than 36 0/7 weeks gestation who presented with all 5 of the criteria described
in our previous report (sentinel event, acidosis less than 7 at birth or within the first hour, Apgar score less than 6 at five minutes, neonatal encephalopathy on exam with seizures or hypotonia and no other cause for encephalopathy other than prematurity determined) [10]. In addition, we required the infants to be ventilator dependent due to their encephalopathy, based on our previous observation that all of the preterm infants with long-term adverse neurologic outcomes were ventilator dependent due to apnea and hypotonia. If the baby met criteria, the parents or guardians were approached for consent for study. If parents refused, care was at the discretion of the neonatology team. Cooling was done using the Olympic Cool-Cap® System with the cap initially set at 20◦ C, Cap temperature was gradually reduced with a target cap temperature of 12◦ C. The present study was approved by the local IRB and we obtain FDA IDE permission to use the Cool Cap device off label for selective head cooling G 070204 and reported our intent to carry out the research in Clinical Trails.gov- Record 070984. To avoid moderate or severe systemic hypothermia the rectal temperature was not to go lower than 35◦ C. The plan was for the cap to be applied for 72 hours and then rewarmed to 20◦ C over a four hour period. After the second case which confirmed the difficulty of obtaining the target cap temperature we resubmitted the protocol to both the FDA and the IRB requesting a change to allow the use of a warming blanket in conjunction with the Cooling Cap. This change was approved and applied to the final two subjects.
3. Results Four patients were enrolled in our pilot study. Case 1: 35 1/7 week gestation infant with birth weight of 2.17 kg • Birth history complicated by a total abruption of the placenta. Apgar scores were 1/2/2 with a cord gas pH of 6.6 with a base deficit of −32. Neurologic exam revealed a hypotonic infant with spontaneous respirations with no response to gentle stimuli, pupils normal but gag depressed, classified as Sarnat 2. After enrollment, cooling cap was placed and we were unable to cool cap below 19.5◦ C. We tried 3 times over a 2 hours period. During that time the baby was under sterile towels and each time the cap was low-
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
ered the baby’s rectal temperature would drop below the target of 36◦ C. We were unsuccessful in attempting to lower cap temperature without inducing hypothermia. Bicycling movement felt to be seizures on EEG began 6 hours after cooling trial abandoned, the infant survived after a threeweek course in the NICU. At 4 years of age he is microcephalic, unable to eat, has severe mental retardation, cerebral palsy, and epilepsy. Case 2: 32 week gestation infant with birth weight of 2.0 kg • Mother had non-accidental trauma and abruption (mother died from her injuries). Baby was born by emergency cesarean section with Apgar scores of 0/0/1 and a cord gas pH of 6.86. Neurologic exam infant with apnea and decreased tone, spontaneous breathing, gag intact, responsive to stimulation with withdrawal, lip smacking correlated with seizure felt to have Sarnat 2 encephalopathy. After obtaining permission from maternal grandmother we enrolled the infant and placed the Cool Cap. The temperature of the circulating water was reduced to 12◦ C. However, the rectal temperature dropped requiring the cap temperature to be increased. It took 16 hours to obtain target cap temperature despite overhead warmer. The infant survived. At 4 months of age, the patient was dependent upon gastrostomy feeds and had global increase in tone. By four years of age, the patient has severe athetoid cerebral palsy and is functioning at 6 month developmental level. Case 3: 33 week gestation infant with birth weight of 2.8 kg • Baby was in breech presentation with loss of FHR 10 minutes prior to delivery. Apgar scores were 0/0/3 with a blood gas pH 6.69. On exam at admission, fixed pinpoint pupils, diffuse clonus was noted and patient was without respiratory effort. Assigned Sarnat 3 stage HIE. By using the modified protocol with a warming blanket we were able to decrease cap temperature below 12◦ C in 12 hours and to 10.5◦ C without experiencing systemic hypothermia as measured by rectal temperature. However, the parents and physician team withdrew cooling at 24 hours due to poor prognosis based on neurologic exam and flat EEG. The infant was taken off the cooling cap, transitioned to comfort care status, and died three days later of
49
respiratory failure. Upon review it was determined that the death was unrelated to cooling. Case 4: 32 week gestation infant with a birth weight of 1.78 kg • Infant with breech presentation complicated by an abruption, bleeding and decreased fetal movement of two hours duration. Apgar scores were 1/1/6 with a cord gas pH of 6.87. Epinephrine was given twice. After 8 minutes the heart rate increased to over 100. On admission, the infant was Sarnat stage 2 with hypotonia and lethargy but no active seizures, responded to stimulation, spontaneous breathing with ventilation support, she had a low rectal temperature of 33.6◦ C (without external cooling). By applying the warming blanket and the radiant warmer we were able to obtain a cap temperature of 12◦ C within 6 hours with a rectal temperature also within target. The infant was extubated on day 2. On day 3, the infant developed an extensive pulmonary hemorrhage requiring resuscitation and reintubation. The infant was noted to have a grade 3 IVH on day three after the pulmonary hemorrhage event. PT and PTT and fibrinogen testing was normal. A large patent ductus arteriosus was felt to be contributory to the pulmonary hemorrhage. The baby subsequently survived and was discharged after receiving a shunt for post hemorrhagic hydrocephalus. At three years of age the Bayley Scale of infant development cognitive score was 90 and motor score was 85 with diagnosis of moderate cerebral palsy.
4. Discussion Our understanding of the pathogenesis of neuronal damage in HIE is evolving even in the term population. In the acute phase of neuronal injury, hypoxia induces anaerobic metabolism, which leads to an accumulation of lactic acid, glutamate, calcium and free radicals within the tissues and a breakdown of normal cellular processes, causing cell death [15]. While it is difficult for clinicians to prevent the primary phase of neurological cell death, evidence has accumulated that there is potential to intervene during the delayed phase of brain injury [16]. Therapeutic hypothermia has emerged as an important intervention to improve neurological outcomes following hypoxic-ischemic events. Fur-
50
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
thermore, multiple studies have shown benefits of hypothermia in term neonates [16–17]. According to the Cochrane review, therapeutic hypothermia results in statistically significant improvements in neurological outcomes and mortality rates at 18 months of age [17]. In a fetal sheep model of preterm HIE, Gunn and Bennet demonstrated that the preterm animals had impaired oxidative metabolism compared to the term animals [12]. This may suggest that the brain tissue of preterm infants has less neuroprotective capacity following ischemic insult as compared to the term infant. Evidence is also accumulating that preterm infants are more susceptible to hypoxic-ischemic damage to the white matter of the brain. Oligodendrocytes are susceptible to oxidative damage in a maturationdependent fashion. According to Back et al. [20] immature oligodendrocytes (preOLs) are highly susceptible to ischemic damage during the period of 23 to 32 weeks postconceptional age. The mature forms of oligodendrocytes appear to be more resistant to the type of damage found in HIE. Additionally, the immature cerebrovascular system in preterm infants makes the white matter more susceptible to ischemia following a hypoxic-ischemic event due to pressure passive circulation. These four cases illustrate the challenge of trying to apply therapeutic hypothermia to preterm infants. The diagnosis is uncertain, the hypoxic ischemic injury is frequently due to catastrophic abruption events, and the infant is more susceptible to multiple adverse effects of prematurity and hypothermia. In our small series all four of the infants either died, or had long term significant neurologic injury. This compares to 58% adverse outcomes in our previous series of 12 preterm infants [10]. The baseline rate of cerebral palsy (CP) that is much higher in the preterm population compared to term infants (rate of CP in neonatal survivors in preterm infants is 3–80/1000 compared to 1/1000 in term survivors) [21]. A Swedish study of 19 year-old boys reported fifty-five times the normal risk of CP for boys with VLBW (95% CI 40.8–75.2) [5]. TH is being used in preterm infants. We reviewed the TOBY registry and the Pediatrix registry, and reported in 2011 [22] that of 1453 cooled infants, 48 (3.3%) were 32–35 weeks gestation. Between 2006 and 2009, the VON Encephalopathy registry also reported that 4.2% of 1024 cooled infants were less than 36 weeks gestation (personal communication). To help determine what was happening in practice we sent a survey
to the members of the perinatal section of the AAP (373 replies represented a 21% overall response rate). To the question “Do you cool infants less than 36 weeks gestation with hypoxic ischemic injury,” 114 (31%) responded: 5% saying “yes” and 26% saying “sometimes”. It is apparent that despite the difficulties with the diagnosis, preterm infants are thought to experience acute perinatal hypoxic events, but there is neither consensus nor adequate evidence for how to ameliorate CNS injury in this population. In this pilot study we did demonstrate that it is possible to obtain cap temperatures as low as 12◦ C without lowering the rectal temperature below 36◦ C when adding a combination of radiant heat and a warming blanket. Determining whether this combination results in actual cooling of the tissues of the brain and then determining whether such cooling results in an amelioration or on-going CNS secondary injury, is not possible at this time. The reports on piglets by Thoresen [13, 14] would suggest that the brain tissues are cooled in the piglet model. We have tried MRI thermography to see if there is a way to visualize the distribution of temperature in the brain undergoing cooling, and to compare those images with later outcomes, but have not been able to complete those studies [23]. Most concerning Dr. Thoresen has performed recent studies that suggest that cooling without systemic hypothermia has no beneficial effect on brain pathology (personal communication). It may be that the benefits of therapeutic hypothermia that have been documented in term infants are dependent upon the systemic cooling and not just local brain cooling. Systemic hypothermia may decrease overall circulating inflammatory cytokines which play a role in the secondary phase of brain injury and thus local brain cooling might be ineffective without systemic cooling. The authors cannot recommend applying therapeutic hypothermia to preterm infants outside of clinical trials. After performing this pilot study of cooling in preterm infants, it is apparent that there are obstacles to studying cooling in preterm infants that may be insurmountable. The number of centers needed for a trial that tests efficacy would be prohibitive given that during the time of our study we estimated 70,000 deliveries in our referral region, and we identified only 6 infants (two of whom were not enrolled in our pilot study and the four cases we report). The incidence of HIE in preterm infants seems to be similar to the incidence in term infants, 1/1000 preterm births, but there are only
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
10% as many preterm births at 32–35 weeks gestation as term births. Thus, in order to perform a trial with 200 babies in each cohort we estimate it would require over 2 million total births to identify a sufficient number of preterm infants meeting the definition of HIE for a randomized trial of adequate power. A reliable biomarker of evolving CNS injury might make such a trial feasible. A second major obstacle is that the ability to determine safety of TH is more challenging since there are poor outcomes in preterm asphyxiated infants as well as un-asphyxiated preterm infants who are cold. As speculation, it may be more appropriate to study other emerging therapies that have the potential to ameliorate HIE such as erythropoietin analogues, xenon or magnesium, which have been proven safe, or at least not shown to be harmful in preterm infants, although efficacy data is obviously lacking. In conclusion, it is physically possible using a combination of radiant heat and a warming blanket to circulate cold water around the skull of a preterm infant without lowering the rectal temperature. However, there is no evidence that this is either safe or beneficial for the preterm with HIE.
References [1]
[2]
[3]
[4]
[5] [6]
[7]
Levene ML, Kornberg J, Williams THC. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Human Dev 1985;11:21-6. Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard B, Edwards AD, et al. Determinants of Outcomes after Head Cooling for Neonatal Encephalopathy. Pediatrics 2007;119:912. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson, JE, McDonald, SA, Donovan, EF, et al. Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. N Engl J Med 2005;353:1574-84. Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. TOBY Study Group. N Engl J Med 2014;371:140. Ericson A, Kallen B. Very low birthweight boys at 19. Arch Dis Child Fetal Neonatal Ed 1998;78:F171-74. Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics 1958;22:876-86. McCall EM, Alderdice FA, Halliday HL, Jenkins JG, Vohra S. Interventions to prevent hypothermia at birth in preterm
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21] [22]
[23
51
and/or low birthweight infants. Cochrane Database Syst Rev 2008;1:3-4. Miller SS, Lee HC, Gould JB. 2011. Hypothermia in very low birth weight infants: Distribution, risk factors and outcomes. J Perinatol 2011;31:s49-s56. The American College of Obstetricians and Gynecologists. Neonatal encephalopathy and cerebral palsy: Defining the pathogenesis and pathophysiology. Washington, DC; 2003. pp. 3-4. Walsh WF, Schmidt JW. Hypoxic-ischemic encephalopathy in preterm infants. J Neonatal Perinatal Med 2010;3: 277-84. Salhab WA, Perlman JM. Severe fetal academia and subsequent neonatal encephalopathy in the larger premature infant. Pediatric Neurol 2005;32:25-9. Gunn AJ and Bennet L. Brain Cooling for Preterm Infants. Clin Perinatol 2008;35:735-48. Tooley JR, Eagle RC, Satas S, Thoresen M. Significant head cooling can be achieved while maintaining normothermia in the newborn piglet. Arch Dis Child Fetal Neonatal Ed 2005;90:F262-6. Tooley J, Satas S, Eagle R, Silver IA, Thoresen M. Significant Selective Head Cooling Can be Maintained Long-Term After Global Hypoxia Ischemia in Newborn Piglets. Pediatrics 2002;109(4):643-9. Perlman JM. Intervention Strategies for Neonatal Hypoxic-Ischemic Cerebral Injury. Clinical Therapeutics 2006;28(9):1353-1365. Gunn AJ, Gluckman PD, and Gunn TR. Selective Head Cooling in Newborn Infants After Perinatal Asphyxia: A Safety Study Pediatrics 1998;102(4):885-92. Jacob S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;17:CD003311. Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in asphyxiated human newborn infants: A retrospective chart analysis of physiological and adverse effects. Intensive Care Med 1999;25:1111-7. Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 2000;106:684-94. Back SA, Riddle A, and McClure MM. MaturationDependent Vulnerability of Verinatal White Matter in Premature Birth. Stroke 2007;38:724-730. McIntyre S, Morgan C, Walter K, Novak I. Cerebral palsydon’t delay. Dev Disabil Res Rev 2011;17(2):114-29. Walsh WF, Azzopardi D, Hobson A, Clark R. Survival of Infants between 32–35 weeks gestation treated with Hypothermia for Hypoxic Ischemic Encephalopathy (HIE). PAS 2011;3675.4. Walsh WF, Moore JE, Pradhan S, Wuschensky C, Gatenby JC, Welch EB. Magnetic Resonance Thermal Imaging. The 5th International Conference on Brain Monitoring and Neuroprotection in the Newborn 2010.
Journal of Neonatal-Perinatal Medicine 8 (2015) 47–51 DOI 10.3233/NPM-15814078 IOS Press
Original Research
Report of a pilot study of Cooling four preterm infants 32–35 weeks gestation with HIE William F. Walsha,∗ , David Butlerb and John W. Schmidtc a Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt Nashville,
TN, USA b Department of Pediatrics, Children’s Mercy Hospital, Kansas City, MO, USA c Joint Division of Newborn Medicine, Creighton University Medical Center, Omaha, NE, USA
Received 20 August 2014 Revised 6 November 2015 Accepted 17 December 2014
Abstract. This report reviews the use of the Cool-Cap device to apply selective therapeutic hypothermia to the brain of preterm infants, without causing systemic hypothermia. Four infants, 32–35 weeks gestation, with suspected Hypoxic Ischemic Encephalopathy (HIE) received treatment aimed at providing selective brain cooling. It was not possible to apply cold circulating water to the scalp of the preterm infant without systemic hypothermia unless a warming blanket was also used. All infants had severe HIE and all had either death, or neurologic disability despite cooling attempts. Therapeutic hypothermia cannot be recommended at this time for preterm infants outside clinical trials. Keywords: Hypoxic ischemic encephalopathy, therapeutic hypothermia, cool cap
1. Introduction Hypoxic ischemic encephalopathy (HIE) treatments have been investigated for term infants. HIE, occurring in 2.9–9/1000 term births, is recognized as a major cause of mortality and morbidity in the newborn worldwide [1]. However, there is little research regarding HIE in preterm infants. The majority of term baby HIE occurs secondary to loss of oxygenation due to etiologies such as abruption, prolapsed cord, uterine rupture, ∗ Corresponding author: Dr. William F. Walsh, Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children’s Hospital at Vanderbilt, 2200 Children’s Way, Nashville, TN 37232, USA. Tel.: +1 615 322 0545; Fax: +1 615 343 1883; E-mail: [email protected].
placental insufficiency, and compression of the cord [2]. Adverse neurological outcomes following perinatal anoxic brain injury, such as cerebral palsy, seizure disorders, and neurodevelopmental insults have been reported in over 60% of infants that meet criteria [2]. Furthermore, HIE results in death secondary to multiorgan failure within the neonatal period in 20–30% of term infants with significant asphyxia [2]. Therapeutic hypothermia (TH) is clearly established to improve the medium and long-term outcomes from moderate to severe HIE at term neuroprotective in term infants [3, 4]. Preterm infants were intentionally excluded from the early randomized trials of TH for a number of reasons. HIE is difficult to diagnose in preterm infants due to the confounding effects of prematurity itself on the
1934-5798/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved
48
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
neurologic examination, Apgar scores, and the laboratory findings which have been used in term infants to diagnose HIE. In addition, the effects of premature delivery and confounding injuries during prolonged neonatal intensive care on the immature central nervous systems result in neurologic injuries such as periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH). Determining the timing and mechanism of CNS injury in preterm infants is not possible at this time since acquired insults confound the long-term neurologic outcomes in preterm infants [5]. Thus it is difficult to determine any additive impact of perinatal HIE on the neurodevelopmental outcomes of preterm infants. Finally, hypothermia is universally recognized as an adverse experience for the preterm infant associated with increased mortality and morbidity in numerous reports since the original work by Silverman [6]. The California Quality Care Collaborative reported an increased risk of death and IVH in infants less than 1500 grams with moderate short term hypothermia and no one has looked at safety of intentional prolonged hypothermia [7, 8]. For these reasons, the definition of HIE by ACOG and the AAP states that HIE is only applicable for infants >34 completed weeks of gestation [9] and to date all studies of TH have excluded infants less than 35 weeks gestation. We, and others, reported on the definition of HIE in preterm infants [10, 11] and felt that with careful evaluation we could successfully define the preterm infant 32–35 weeks gestation with HIE in order to take the first step toward providing therapy to ameliorate long-term injury. Animal models of hypothermia to prevent progressive CNS injury in preterms are promising. Alistair Gunn demonstrated the potential of hypothermia to ameliorate brain injury in a preterm lamb equivalent to about 29 week’s gestation [12]. Importantly, Thoresen et al. published an intriguing report on the ability to provide selective CNS cooling without systemic hypothermia in a piglet model [13, 14]. Based on these reports we designed a pilot study to determine if it was feasible to cool the scalp and potentially the brain of a preterm human infant without causing systemic hypothermia.
2. Methods Eligible infants were babies over 1500 grams and over 32 0/7 weeks and less than 36 0/7 weeks gestation who presented with all 5 of the criteria described
in our previous report (sentinel event, acidosis less than 7 at birth or within the first hour, Apgar score less than 6 at five minutes, neonatal encephalopathy on exam with seizures or hypotonia and no other cause for encephalopathy other than prematurity determined) [10]. In addition, we required the infants to be ventilator dependent due to their encephalopathy, based on our previous observation that all of the preterm infants with long-term adverse neurologic outcomes were ventilator dependent due to apnea and hypotonia. If the baby met criteria, the parents or guardians were approached for consent for study. If parents refused, care was at the discretion of the neonatology team. Cooling was done using the Olympic Cool-Cap® System with the cap initially set at 20◦ C, Cap temperature was gradually reduced with a target cap temperature of 12◦ C. The present study was approved by the local IRB and we obtain FDA IDE permission to use the Cool Cap device off label for selective head cooling G 070204 and reported our intent to carry out the research in Clinical Trails.gov- Record 070984. To avoid moderate or severe systemic hypothermia the rectal temperature was not to go lower than 35◦ C. The plan was for the cap to be applied for 72 hours and then rewarmed to 20◦ C over a four hour period. After the second case which confirmed the difficulty of obtaining the target cap temperature we resubmitted the protocol to both the FDA and the IRB requesting a change to allow the use of a warming blanket in conjunction with the Cooling Cap. This change was approved and applied to the final two subjects.
3. Results Four patients were enrolled in our pilot study. Case 1: 35 1/7 week gestation infant with birth weight of 2.17 kg • Birth history complicated by a total abruption of the placenta. Apgar scores were 1/2/2 with a cord gas pH of 6.6 with a base deficit of −32. Neurologic exam revealed a hypotonic infant with spontaneous respirations with no response to gentle stimuli, pupils normal but gag depressed, classified as Sarnat 2. After enrollment, cooling cap was placed and we were unable to cool cap below 19.5◦ C. We tried 3 times over a 2 hours period. During that time the baby was under sterile towels and each time the cap was low-
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
ered the baby’s rectal temperature would drop below the target of 36◦ C. We were unsuccessful in attempting to lower cap temperature without inducing hypothermia. Bicycling movement felt to be seizures on EEG began 6 hours after cooling trial abandoned, the infant survived after a threeweek course in the NICU. At 4 years of age he is microcephalic, unable to eat, has severe mental retardation, cerebral palsy, and epilepsy. Case 2: 32 week gestation infant with birth weight of 2.0 kg • Mother had non-accidental trauma and abruption (mother died from her injuries). Baby was born by emergency cesarean section with Apgar scores of 0/0/1 and a cord gas pH of 6.86. Neurologic exam infant with apnea and decreased tone, spontaneous breathing, gag intact, responsive to stimulation with withdrawal, lip smacking correlated with seizure felt to have Sarnat 2 encephalopathy. After obtaining permission from maternal grandmother we enrolled the infant and placed the Cool Cap. The temperature of the circulating water was reduced to 12◦ C. However, the rectal temperature dropped requiring the cap temperature to be increased. It took 16 hours to obtain target cap temperature despite overhead warmer. The infant survived. At 4 months of age, the patient was dependent upon gastrostomy feeds and had global increase in tone. By four years of age, the patient has severe athetoid cerebral palsy and is functioning at 6 month developmental level. Case 3: 33 week gestation infant with birth weight of 2.8 kg • Baby was in breech presentation with loss of FHR 10 minutes prior to delivery. Apgar scores were 0/0/3 with a blood gas pH 6.69. On exam at admission, fixed pinpoint pupils, diffuse clonus was noted and patient was without respiratory effort. Assigned Sarnat 3 stage HIE. By using the modified protocol with a warming blanket we were able to decrease cap temperature below 12◦ C in 12 hours and to 10.5◦ C without experiencing systemic hypothermia as measured by rectal temperature. However, the parents and physician team withdrew cooling at 24 hours due to poor prognosis based on neurologic exam and flat EEG. The infant was taken off the cooling cap, transitioned to comfort care status, and died three days later of
49
respiratory failure. Upon review it was determined that the death was unrelated to cooling. Case 4: 32 week gestation infant with a birth weight of 1.78 kg • Infant with breech presentation complicated by an abruption, bleeding and decreased fetal movement of two hours duration. Apgar scores were 1/1/6 with a cord gas pH of 6.87. Epinephrine was given twice. After 8 minutes the heart rate increased to over 100. On admission, the infant was Sarnat stage 2 with hypotonia and lethargy but no active seizures, responded to stimulation, spontaneous breathing with ventilation support, she had a low rectal temperature of 33.6◦ C (without external cooling). By applying the warming blanket and the radiant warmer we were able to obtain a cap temperature of 12◦ C within 6 hours with a rectal temperature also within target. The infant was extubated on day 2. On day 3, the infant developed an extensive pulmonary hemorrhage requiring resuscitation and reintubation. The infant was noted to have a grade 3 IVH on day three after the pulmonary hemorrhage event. PT and PTT and fibrinogen testing was normal. A large patent ductus arteriosus was felt to be contributory to the pulmonary hemorrhage. The baby subsequently survived and was discharged after receiving a shunt for post hemorrhagic hydrocephalus. At three years of age the Bayley Scale of infant development cognitive score was 90 and motor score was 85 with diagnosis of moderate cerebral palsy.
4. Discussion Our understanding of the pathogenesis of neuronal damage in HIE is evolving even in the term population. In the acute phase of neuronal injury, hypoxia induces anaerobic metabolism, which leads to an accumulation of lactic acid, glutamate, calcium and free radicals within the tissues and a breakdown of normal cellular processes, causing cell death [15]. While it is difficult for clinicians to prevent the primary phase of neurological cell death, evidence has accumulated that there is potential to intervene during the delayed phase of brain injury [16]. Therapeutic hypothermia has emerged as an important intervention to improve neurological outcomes following hypoxic-ischemic events. Fur-
50
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
thermore, multiple studies have shown benefits of hypothermia in term neonates [16–17]. According to the Cochrane review, therapeutic hypothermia results in statistically significant improvements in neurological outcomes and mortality rates at 18 months of age [17]. In a fetal sheep model of preterm HIE, Gunn and Bennet demonstrated that the preterm animals had impaired oxidative metabolism compared to the term animals [12]. This may suggest that the brain tissue of preterm infants has less neuroprotective capacity following ischemic insult as compared to the term infant. Evidence is also accumulating that preterm infants are more susceptible to hypoxic-ischemic damage to the white matter of the brain. Oligodendrocytes are susceptible to oxidative damage in a maturationdependent fashion. According to Back et al. [20] immature oligodendrocytes (preOLs) are highly susceptible to ischemic damage during the period of 23 to 32 weeks postconceptional age. The mature forms of oligodendrocytes appear to be more resistant to the type of damage found in HIE. Additionally, the immature cerebrovascular system in preterm infants makes the white matter more susceptible to ischemia following a hypoxic-ischemic event due to pressure passive circulation. These four cases illustrate the challenge of trying to apply therapeutic hypothermia to preterm infants. The diagnosis is uncertain, the hypoxic ischemic injury is frequently due to catastrophic abruption events, and the infant is more susceptible to multiple adverse effects of prematurity and hypothermia. In our small series all four of the infants either died, or had long term significant neurologic injury. This compares to 58% adverse outcomes in our previous series of 12 preterm infants [10]. The baseline rate of cerebral palsy (CP) that is much higher in the preterm population compared to term infants (rate of CP in neonatal survivors in preterm infants is 3–80/1000 compared to 1/1000 in term survivors) [21]. A Swedish study of 19 year-old boys reported fifty-five times the normal risk of CP for boys with VLBW (95% CI 40.8–75.2) [5]. TH is being used in preterm infants. We reviewed the TOBY registry and the Pediatrix registry, and reported in 2011 [22] that of 1453 cooled infants, 48 (3.3%) were 32–35 weeks gestation. Between 2006 and 2009, the VON Encephalopathy registry also reported that 4.2% of 1024 cooled infants were less than 36 weeks gestation (personal communication). To help determine what was happening in practice we sent a survey
to the members of the perinatal section of the AAP (373 replies represented a 21% overall response rate). To the question “Do you cool infants less than 36 weeks gestation with hypoxic ischemic injury,” 114 (31%) responded: 5% saying “yes” and 26% saying “sometimes”. It is apparent that despite the difficulties with the diagnosis, preterm infants are thought to experience acute perinatal hypoxic events, but there is neither consensus nor adequate evidence for how to ameliorate CNS injury in this population. In this pilot study we did demonstrate that it is possible to obtain cap temperatures as low as 12◦ C without lowering the rectal temperature below 36◦ C when adding a combination of radiant heat and a warming blanket. Determining whether this combination results in actual cooling of the tissues of the brain and then determining whether such cooling results in an amelioration or on-going CNS secondary injury, is not possible at this time. The reports on piglets by Thoresen [13, 14] would suggest that the brain tissues are cooled in the piglet model. We have tried MRI thermography to see if there is a way to visualize the distribution of temperature in the brain undergoing cooling, and to compare those images with later outcomes, but have not been able to complete those studies [23]. Most concerning Dr. Thoresen has performed recent studies that suggest that cooling without systemic hypothermia has no beneficial effect on brain pathology (personal communication). It may be that the benefits of therapeutic hypothermia that have been documented in term infants are dependent upon the systemic cooling and not just local brain cooling. Systemic hypothermia may decrease overall circulating inflammatory cytokines which play a role in the secondary phase of brain injury and thus local brain cooling might be ineffective without systemic cooling. The authors cannot recommend applying therapeutic hypothermia to preterm infants outside of clinical trials. After performing this pilot study of cooling in preterm infants, it is apparent that there are obstacles to studying cooling in preterm infants that may be insurmountable. The number of centers needed for a trial that tests efficacy would be prohibitive given that during the time of our study we estimated 70,000 deliveries in our referral region, and we identified only 6 infants (two of whom were not enrolled in our pilot study and the four cases we report). The incidence of HIE in preterm infants seems to be similar to the incidence in term infants, 1/1000 preterm births, but there are only
W.F. Walsh et al. / Cooling preterm infants 32–35 weeks gestation with HIE
10% as many preterm births at 32–35 weeks gestation as term births. Thus, in order to perform a trial with 200 babies in each cohort we estimate it would require over 2 million total births to identify a sufficient number of preterm infants meeting the definition of HIE for a randomized trial of adequate power. A reliable biomarker of evolving CNS injury might make such a trial feasible. A second major obstacle is that the ability to determine safety of TH is more challenging since there are poor outcomes in preterm asphyxiated infants as well as un-asphyxiated preterm infants who are cold. As speculation, it may be more appropriate to study other emerging therapies that have the potential to ameliorate HIE such as erythropoietin analogues, xenon or magnesium, which have been proven safe, or at least not shown to be harmful in preterm infants, although efficacy data is obviously lacking. In conclusion, it is physically possible using a combination of radiant heat and a warming blanket to circulate cold water around the skull of a preterm infant without lowering the rectal temperature. However, there is no evidence that this is either safe or beneficial for the preterm with HIE.
References [1]
[2]
[3]
[4]
[5] [6]
[7]
Levene ML, Kornberg J, Williams THC. The incidence and severity of post-asphyxial encephalopathy in full-term infants. Early Human Dev 1985;11:21-6. Wyatt JS, Gluckman PD, Liu PY, Azzopardi D, Ballard B, Edwards AD, et al. Determinants of Outcomes after Head Cooling for Neonatal Encephalopathy. Pediatrics 2007;119:912. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson, JE, McDonald, SA, Donovan, EF, et al. Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. N Engl J Med 2005;353:1574-84. Azzopardi D, Strohm B, Marlow N, Brocklehurst P, Deierl A, Eddama O, et al. Effects of hypothermia for perinatal asphyxia on childhood outcomes. TOBY Study Group. N Engl J Med 2014;371:140. Ericson A, Kallen B. Very low birthweight boys at 19. Arch Dis Child Fetal Neonatal Ed 1998;78:F171-74. Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics 1958;22:876-86. McCall EM, Alderdice FA, Halliday HL, Jenkins JG, Vohra S. Interventions to prevent hypothermia at birth in preterm
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21] [22]
[23
51
and/or low birthweight infants. Cochrane Database Syst Rev 2008;1:3-4. Miller SS, Lee HC, Gould JB. 2011. Hypothermia in very low birth weight infants: Distribution, risk factors and outcomes. J Perinatol 2011;31:s49-s56. The American College of Obstetricians and Gynecologists. Neonatal encephalopathy and cerebral palsy: Defining the pathogenesis and pathophysiology. Washington, DC; 2003. pp. 3-4. Walsh WF, Schmidt JW. Hypoxic-ischemic encephalopathy in preterm infants. J Neonatal Perinatal Med 2010;3: 277-84. Salhab WA, Perlman JM. Severe fetal academia and subsequent neonatal encephalopathy in the larger premature infant. Pediatric Neurol 2005;32:25-9. Gunn AJ and Bennet L. Brain Cooling for Preterm Infants. Clin Perinatol 2008;35:735-48. Tooley JR, Eagle RC, Satas S, Thoresen M. Significant head cooling can be achieved while maintaining normothermia in the newborn piglet. Arch Dis Child Fetal Neonatal Ed 2005;90:F262-6. Tooley J, Satas S, Eagle R, Silver IA, Thoresen M. Significant Selective Head Cooling Can be Maintained Long-Term After Global Hypoxia Ischemia in Newborn Piglets. Pediatrics 2002;109(4):643-9. Perlman JM. Intervention Strategies for Neonatal Hypoxic-Ischemic Cerebral Injury. Clinical Therapeutics 2006;28(9):1353-1365. Gunn AJ, Gluckman PD, and Gunn TR. Selective Head Cooling in Newborn Infants After Perinatal Asphyxia: A Safety Study Pediatrics 1998;102(4):885-92. Jacob S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007;17:CD003311. Simbruner G, Haberl C, Harrison V, Linley L, Willeitner AE. Induced brain hypothermia in asphyxiated human newborn infants: A retrospective chart analysis of physiological and adverse effects. Intensive Care Med 1999;25:1111-7. Azzopardi D, Robertson NJ, Cowan FM, Rutherford MA, Rampling M, Edwards AD. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 2000;106:684-94. Back SA, Riddle A, and McClure MM. MaturationDependent Vulnerability of Verinatal White Matter in Premature Birth. Stroke 2007;38:724-730. McIntyre S, Morgan C, Walter K, Novak I. Cerebral palsydon’t delay. Dev Disabil Res Rev 2011;17(2):114-29. Walsh WF, Azzopardi D, Hobson A, Clark R. Survival of Infants between 32–35 weeks gestation treated with Hypothermia for Hypoxic Ischemic Encephalopathy (HIE). PAS 2011;3675.4. Walsh WF, Moore JE, Pradhan S, Wuschensky C, Gatenby JC, Welch EB. Magnetic Resonance Thermal Imaging. The 5th International Conference on Brain Monitoring and Neuroprotection in the Newborn 2010.
